Viral infections are a major cause of disease and death among the world's population. Important viral pathogens include, for example, human immunodeficiency virus-1 (HIV-1), influenza virus, several forms of hepatitis viruses (HAV, HBV, HCV), herpes viruses (HSV, VZV, EBV, CMV) and a whole panel of arthropode-borne viruses, such as yellow fever virus, dengue virus, west nile virus, among others. Several viruses cause chronic diseases that require life-long treatment. HIV-1, the causative agent of AIDS, is one important example of a chronic viral pathogen and is still a major global health problem, with more than 33 million infected individuals worldwide. Other viruses, such as influenza, show pandemic spread on a frequent basis causing tens of thousands deaths around the world almost every year. In addition, many viruses are known to cause cancer, with T-cell leukaemia (HTLV), cervical cancer (HPV) and liver cancer (HBV, HCV) being prominent examples. It is estimated that 10-20% of all cancers are actually of viral origin.
While vaccines or antiviral drugs are available for a number of viruses, no specific antiviral therapy is available for the great majority of viral pathogens. However, antiviral research has grown dramatically in the past two decades, and the antiviral market has an average growth rate of 16.7% and an expected total volume of $29.4 billion in 2015 ($23.4 billion in 2008). The global antiviral market represents about half of the overall anti-infective market. Antivirals are increasingly important in emerging markets and in markets in less-developed countries where prices may be lower but volumes can be greater. These regions of the world often experience the most severe outbreaks of viral pathogens.
Currently (United States) approved antivirals target infections by the human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), influenza virus, and several herpes viruses. HCV, a flavivirus, has been the focus of intense drug discovery efforts. Recently (May 2011) two protease inhibitors (INCIVEK™, Vertex; Victrelis®, Merck) were fully approved by the FDA for the treatment of chronic hepatitis C infection in combination with pegylated interferon and ribavirin. More than 34 further anti-HCV drugs are in various clinical phases.
While HCV has gained much attention in the field of vaccines and antivirals, other members of the same virus family, flaviviruses, lack far behind. While at least a vaccine is available for yellow fever virus (YFV), two other major pathogens of the flavivirus group, dengue virus (DENV) and West Nile (WNV) virus, currently lack any possibility of a specific antiviral intervention. Dengue virus is the most widespread arthropod-borne virus and is expanding its geographical habitat, due to global climate change. Worldwide, there are approximately 2.5 billion people at risk of infection, with an estimated 40-100 million incidences of dengue infection and about 500,000 hospitalizations due to dengue haemorrhagic fever annually. With a third of the world's population at risk of infection, the World Health Organization (WHO) has made it a priority to develop a treatment/vaccine for the past three decades to no avail. The city of Jeddah, Saudi Arabia, for example, has a particularly high risk for the occurrences of dengue due to the high influx of pilgrims from Indonesia, Malaysia, and Thailand (all high-burden dengue countries). WNV causes a fever with possible neurological involvement. The virus has spread globally with several epidemics in the US. The worst outbreak in the US occurred in 2012 with 286 deaths, mainly in the state of Texas. Despite the availability of an effective vaccine, the WHO estimates that there are still 200,000 infections and approximately 30,000 deaths per year related to yellow fever. An infection with YFV can cause a serious hemorrhagic fever. As for DENV and WNV, there is no specific antiviral treatment available for the yellow fever disease.
Hence, a need exists for better antiviral agents, particularly with respect to flaviviruses including West Nile Virus, for example. HIV is another important target.